Analgesic compositions containing buprenorphine

ABSTRACT

An analgesic composition in parenteral unit dosage form or in a unit dosage form suitable for delivery via the mucosa comprising an amount of buprenorphine which is less than the clinical dose required to achieve pain relief and an amount of naloxone such that the ratio by weight of buprenorphine to naloxone is in the range of from 12.5:1 to 27.5:1, or an amount of naltrexone or nalmefene such that the ratio by weight of buprenorphine to naltrexone or nalmefene is in the range of from 12.5:1 to 22.5:1. The analgesic action of the buprenorphine is potentiated by the low dose of naloxone, naltrexone or nalmefene.

CROSS REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of application No. PCT/GB00/04372 filedon 17 Nov. 2000, which claims the benefit of U.S. ProvisionalApplication No. 60/176,208 filed on 14 Jan. 2000.

FIELD OF THE INVENTION

The present invention relates to analgesic compositions, containingbuprenorphine and, in particular, to compositions which containbuprenorphine at a sub-clinical analgesic dose level in combination withnaloxone, naltrexone or nalmefene.

BACKGROUND OF THE INVENTION

Buprenorphine (International Non-proprietary Name forN-cyclopropylmethyl-7α-[1-(S)-hydroxy-1,2,2-trimethylpropyl]6,14-endoethano-6,7,8,14-tetrahydro-nororipavine)has been shown in clinical trials to be a potent opiate partial agonistanalgesic lacking the psychotomimetic effects found with other opiateanalgesics. Buprenorphine effectively relieves moderate to severe painin doses of 0.1 mg or more administered either parenterally orsublingually. The optimum therapeutic range for single doses is 0.3mg–0.6 mg by injection and 0.2 mg–0.8 mg for sublingual tablets.

In animal tests and in man buprenorphine has been shown to have bothagonist (morphine-like) and antagonist properties. However from directdependence studies in animals and in man it has been concluded thatbuprenorphine does not produce significant physical dependence, asindicated by animal self administration studies and by the measurementof euphorigenic effects in human post addicts. However, buprenorphinesuffers from side effects typical of opiate agonists such as nausea andvomiting, constipation and respiratory depression in some patients,although there is a ceiling to its effects on respiratory depression asa direct consequence of its partial agonist properties.

Naloxone (International Non-proprietary Name for1-N-allyl-14-hydroxynorhydromorphinone) is a narcotic antagonist whichhas been incorporated into oral and sublingual preparations of variousopioids in order to protect the preparations from parenteral abuse,whilst maintaining the analgesic effect of the opioid.

GB-A-2150832 describes analgesic compositions in sublingual orparenteral dosage form comprising an active dose of buprenorphine and anamount of naloxone sufficient to prove aversive to a narcotic addict byparenteral administration but insufficient to compromise the analgesicaction of the buprenorphine. Preferably the parenteral dosage formcontains naloxone and buprenorphine within the weight ratio of 1:3 to1:1 and the sublingual form within the ratio 1:2 to 2:1.

Naltrexone (International Non-proprietary Name for1-N-cyclopropylmethyl-14-hydroxynordihydro-morphinone) is a pure opiateantagonist which, when administered orally (50 mg/day) as a maintenancedrug for opiate addicts, blocks the effects of self-administered opiatesand this contributes to the extinction of drug craving.

Nalmefene (International Non-Proprietary Name for(5)-17-(cyclopropylmethyl)-4,5-epoxy-6-methylene-morphinan-3,14-diol) isa structural analogue of naltrexone with opiate antagonist activity.

GB-A-2167633 describes an analgesic composition in parenteral orsublingual unit dosage form comprising an active dose of buprenorphineand an amount of naltrexone sufficient to prove aversive to a narcoticaddict by parenteral administration but insufficient to compromise theanalgesic action of the buprenorphine wherein the dose of buprenorphinein the parenteral form is from about 0.3 mg to about 0.6 mg and in thesublingual form from about 0.1 mg to about 0.4 mg and the weights ofbuprenorphine to naltrexone for the parenteral form are within the ratioof 12:1 to 3:1 and for the sublingual form are within the ratio 4:1 to1:1.

SUMMARY OF THE INVENTION

We have now surprisingly found that sub-clinical dosage levels ofbuprenorphine are potentiated and enhanced by low doses of naloxone ornaltrexone or nalmefene. The interaction between the drugs is asynergistic interaction and more than the additive effects of theseparate drug entities.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is graph showing the results of the tests done according toExample 1.

FIG. 2 is a graph showing the results of the tests done according toExample 2.

FIG. 3 is a graph showing the results of the tests done according toExample 3.

DETAILED DISCLOSURE

Accordingly, the present invention provides in its broadest aspect ananalgesic composition in parenteral unit dosage form or in a unit dosageform suitable for delivery via the mucosa comprising an amount ofbuprenorphine which is less than the clinical dose required to achievepain relief and

-   -   (i) an amount of naloxone such that the ratio by weight of        buprenorphine to naloxone is in the range of from 12.5:1 to        27.5:1, or    -   (ii) an amount of naltrexone or nalmefene such that the ratio by        weight of buprenorphine to naltrexone or nalmefene is in the        range of from 12.5:1 to 22.5:1        whereby the analgesic action of the buprenorphine is potentiated        by the low dose of naloxone, naltrexone or nalmefene.

In a first aspect the present invention provides an analgesiccomposition in parenteral or sublingual unit dosage form or in a unitdosage form suitable for delivery via the mucosa comprising from 15 μgto 200 μg of buprenorphine per unit dose and

-   -   (i) an amount of naloxone such that the ratio by weight of        buprenorphine to naloxone is in the range of from 12.5:1 to        27.5:1, or    -   (ii) an amount of naltrexone or nalmefene such that the ratio by        weight of buprenorphine to naltrexone or nalmefene is in the        range of from 12.5:1 to 22.5:1.

It is to be understood that the terms buprenorphine, naloxone,naltrexone and nalmefene as used herein are meant to cover not only thebases but their pharmaceutically acceptable salts. Particularlypreferred salts are the hydrochlorides.

It is preferable to formulate the compositions in unit dosage forms i.e.physically discrete units containing the appropriate amounts ofbuprenorphine and naloxone, naltrexone or nalmefene, together withpharmaceutically acceptable diluents and/or carriers. Such unit dosageforms for parenteral administration are suitably in the form of ampoulesand for delivery via the mucosa may for example be in the form oftablets for sublingual administration.

The term parenteral is intended to encompass administration of thecompositions by any way other than through the alimentary tract.

The term mucosa is intended to encompass any mucous membrane andincludes oral mucosa, rectal mucosa, vaginal mucosa and nasal mucosa.

Compositions intended for parenteral administration comprise an isotonicsolution of buprenorphine and naloxone, naltrexone or nalmefene insterile water. Conveniently the solution is made isotonic by use ofdextrose and sterilised by autoclaving or by filtration through amembrane filter. The compositions may be administered intramuscularly,intradermally, intraperitonealy, intravenously, intraarterially,subcutaneously or by the epidural route.

Compositions in the form of sublingual tablets contain solubleexcipients such as lactose, mannitol, dextrose, sucrose or mixturesthereof. They will also contain granulating and disintegrating agentssuch as starch, binding agents such as povidone or hydroxypropyl-methylcellulose and lubricating agents such as magnesium stearate.

The compositions for parenteral administration, or for delivery via themucosa, such as by sublingual administration, as detailed above, may beprepared by manufacturing techniques which are well known to thoseskilled in the art.

The compositions of the present invention in unit dosage form preferablycontain the naloxone, naltrexone or nalmefene in an amount such that theratio by weight of buprenorphine to naloxone, naltrexone or nalmefene isin the range of from 15:1 to 20:1.

The compositions of the present invention contain buprenorphine in anamount which is below that required in a unit dose to obtain painrelief. In the human being, dosages of about 40 μg of buprenorphine perkilogram of body weight are required to obtain satisfactory pain reliefin the absence of potentiation. Thus for typical body weights of 50 to80 kg, the dosage would be from 2000 μg to 3200 μg, i.e. from 2 mg to3.2 mg of buprenorphine per day. This would conveniently be administeredas 4 unit doses. The amounts of buprenorphine which are effective in thepresent invention are below the amounts which are effective in theabsence of the potentiating effects of naloxone, naltrexone ornalmefene.

In a second aspect the present invention provides a method for thetreatment of pain in a human or animal subject, which method comprisesthe administration to the human or animal by the parenteral or via themucosa route of from 1.25 μg to 10 μg per kilogram of body weight ofbuprenorphine per day and

-   -   (i) an amount of naloxone such that the ratio by weight of        buprenorphine to naloxone administered is in the range of from        12.5:1 to 27.5:1, or    -   (ii) an amount of naltrexone or nalmefene such that the ratio by        weight of buprenorphine to naltrexone or nalmefene administered        is in the range of from 12.5:1 to 22.5:1.

In a third aspect the present invention provides the use of naloxone,naltrexone or nalmefene in the manufacture of a medicament for thetreatment of pain comprising a sub-clinical amount of buprenorphine,wherein the ratio by weight of buprenorphine to naloxone is in the rangeof from 12.5:1 to 27.5:1 or the ratio by weight of buprenorphine tonaltrexone or nalmefene is in the range of from 12.5:1 to 22.5:1.

The ratios for the potentiation of the sub-clinical dosages ofbuprenorphine by low doses of the opiate antagonists were determined bythe University Department of Anaesthesia, Addenbrookes Hospital,Cambridge according to the paw withdrawal method of Hargreaves, K. M.,Dubner, R., Brown, F., Flores, C. and Joris, J.: A New and SensitiveMethod for Measuring Thermal Nociception in Cutaneous Hyperalgesia. Pain32: 77–88, 1988. This method enables the researcher to discern aperipherally mediated response to thermal stimulation caused by drugs inthe unrestrained rat.

The results were obtained using a BASILE Plantar Test Device (UgoBasile, Comero, Italy). It basically consists of a movable I.R.(infrared) generator placed below a glass pane upon which the operatorplaces the rat. A Perspex enclosure defines the space within which theanimal is unrestrained. It is divided into three compartments, whichhelps the operator to carry out rapid “screening” work: up to three ratscan be tested with no appreciable delay inbetween.

The operator positions the I.R. Generator directly beneath the hind pawof the rat and activates both the I.R. Source and a reaction timecounter. When the rat feels pain and withdraws its paw, the I.R.Generator is automatically switched off and the timer stops, determiningthe withdrawal latency.

The effects of buprenorphine at various dosages, naloxone at variousdosages, naltrexone at various dosages and buprenorphine in combinationwith naloxone or naltrexone at various dosages were determined bytesting adult rats in which peripheral mononeuropathy was produced byplacing three loosely constrictive ligatures around the common sciaticnerve. The testing was carried out on the eighth day following theoperative procedure.

In order to determine a baseline for comparison purposes, rats weresubjected to the Hargreaves paw withdrawal test before the subcutaneousinjection of the various drugs or drug combinations being tested. Therats were then injected subcutaneously with the particular drug or drugcombination being tested and the percentage change in time for the ratto withdraw its paw from the thermal stimulation, in comparison with thebaseline, was recorded as a percentage in paw withdrawal latency.

The invention is further described with reference to the followingExamples.

Methods

Surgery

Lister Hooded rats (180–200 g) were anaesthetised with halothane and theleft sciatic nerve was loosely ligated with 3 chromic cat gut sutures toinduce a neuropathy.

Rats were left to recover for one week after the procedure beforecommencing behavioural testing.

Drug Preparation

The drugs (buprenorphine, naloxone and naltrexone) were prepared freshlyin water at a concentration of 1 mg/ml. The stocks were then diluted insaline to obtain the different concentrations used in the study.

Drugs were injected sub-cutaneously in the fold of the neck.

Testing

After 8 days, thermal nociceptive threshold, as determined by hindpawwithdrawal latency, was measured using a plantar test (Ugo Basile,Comero, Italy). Prior to testing, the rat was placed in the Perspex boxand allowed 5 minutes to habituate. The heat source was positioned underthe plantar surface of one hind paw at random and activated. Thisinitiated a timing circuit which measured the time interval between theapplication of the light beam and the withdrawal of the hind paw. Thisvalue was assigned as the withdrawal latency.

Paw withdrawal latency was determined before injection and at differenttimes after injection. Three measurements were taken per paw.

EXAMPLE 1

The effects of buprenorphine and buprenorphine/naloxone at weight ratiosof 20:1 and 15:1 were determined at various doses of buprenorphineexpressed as μg/kg of body weight of the drug administeredsubcutaneously to rats (n=3).

The results of these tests are given in FIG. 1. The potentiation ofsub-clinical doses of buprenorphine by low dose naloxone can be clearlyseen from the graph of FIG. 1. Both of the buprenorphine/naloxonecombinations showed marked increases in pain withdrawal latencies atboth weight ratios where the buprenorphine dose was 1.25 μg and 2.5 μg,compared to buprenorphine alone which had no significant effect at thesedosage levels.

EXAMPLE 2

Buprenorphine was administered to rats (n=6) at a dosage level of 2.5μg/kg of body weight of the rats. Buprenorphine was co-administeredsubcutaneously with either naloxone or naltrexone at various weightratios ranging from 5:1 to 30:1. In order to provide appropriatebaseline points naloxone and naltrexone alone were also administeredsubcutaneously to rats at the same dosage levels as those used in thecombined treatments.

The results are given in FIG. 2 from which the potentiation of thesub-clinical doses of buprenorphine by naloxone or naltrexone can beclearly seen.

EXAMPLE 3

To investigate the duration of action of several ratios (10:1, 15:1 and20:1 buprenorphine:naloxone, with a fixed dose of buprenorphine) theeffect on PWL was followed over a 26 hour period following subcutaneousinjection. The results are given in FIG. 3 from which it can be seenthat the effect was already maximal after 40 minutes and then decreasedsharply over 6 hours. However at 26 hours a residual effect was stillvisible, although this was not statistically significant. The maximaleffect of each ratio (40 min) was compatible with the results shown inFIG. 2. The effect observed with the 10:1 ratio combination was notstatistically significant.

EXAMPLE 4

A parenteral formulation having the following composition:

mg/ml. Buprenorphine HCl 0.1 Naloxone HCl 0.0067 Anhydrous dextrose 50.0Hydrochloric acid to pH 4.0 Water for injection to 1.0 mlwas prepared by dissolving dextrose, buprenorphine hydrochloride andnaloxone hydrochloride in that order with stirring, in about 95% batchvolume of Water for Injection. The acidity of the solution was adjustedto pH 4.0 by the addition of 0.1M hydrochloric acid, and the solutionwas made up to volume with Water for Injection. The solution wasfiltered through a 0.22 μm membrane filter and transferred to sterilised1 ml or 2 ml glass ampoules containing 1 ml or 2 ml of the solution. Theampoules were sealed and the product sterilised by autoclaving.

EXAMPLE 5

The formulation of Example 4 was varied by using 0.005 mg/ml of naloxonehydrochloride instead of 0.0667 mg/ml.

EXAMPLE 6

The formulation of Example 4 was modified with 0.0067 mg/ml ofnaltrexone hydrochloride substituted for the naloxone hydrochloride ofExample 1.

EXAMPLE 7

The formulation of Example 4 was modified with 0.005 mg/ml of naltrexonehydrochloride substituted for the naloxone hydrochloride of Example 1.

EXAMPLE 8

The formulation of Example 4 was modified with 0.0067 mg/ml of nalmefenehydrochloride substituted for the naloxone hydrochloride of Example 4.

EXAMPLE 9

The formulation of Example 4 was modified with 0.0005 mg/ml of nalmefenehydrochloride substituted for the naloxone hydrochloride of Example 4.

EXAMPLE 10

A sublingual tablet having the following composition:

mg/tablet Buprenorphine HCl 0.1 Naloxone HCl 0.0067 Lactose 31.2433Mannitol 18.0 Maize starch 9.0 Povidone 1.2 Magnesium stearate 0.45 60.0was prepared by screening all the materials with the exception of themagnesium stearate through a 750 μm sieve and blending them together.The mixed powders were then subjected to an aqueous granulationprocedure and dried at 50° C. The resulting granules were forced througha 750 μm sieve and blended with magnesium stearate (pre-sieved through a500 μm sieve). The tablet granules were compressed to yield tablets of5.56 mm diameter and weight 60 mg.

EXAMPLE 11

The formulation of Example 10 was varied by using 0.005 mg/tablet ofnaloxone hydrochloride and adjusting the weight of lactose.

EXAMPLE 12

The formulation of Example 10 was modified with 0.0067 mg/tablet ofnaltrexone hydrochloride substituted for the naloxone hydrochloride ofExample 10.

EXAMPLE 13

The formulation of Example 10 was modified with 0.005 mg/tablet ofnaltrexone hydrochloride substituted for the naloxone hydrochloride ofExample 10.

EXAMPLE 14

The formulation of Example 10 was modified with 0.0067 mg/tablet ofnalmefene hydrochloride substituted for the naloxone hydrochloride ofExample 10.

EXAMPLE 15

The formulation of Example 10 was modified with 0.005 mg/tablet ofnalmefene hydrochloride substituted for the naloxone hydrochloride ofExample 10.

EXAMPLE 16

A suppository having the following composition:

mg/suppository Buprenorphine HCl 0.1 Naloxone HCl 0.0067 Gelatin 200Glycerin 700 Deionised water 89.9was prepared by mixing the ingredients together and melting them atbetween 60° C. and 70° C. The melted mass is poured into a disposablemould of plastic material in which the suppositories are cast and remainenclosed until removed by the patient.

EXAMPLE 17

The formulation of Example 16 was varied by using 0.005 mg/suppositoryof naloxone hydrochloride.

EXAMPLE 18

The formulation of Example 16 was modified with 0.0067 mg/suppository ofnaltrexone hydrochloride substituted for the naloxone hydrochloride ofExample 16.

EXAMPLE 19

The formulation of Example 16 was modified with 0.005 mg/suppository ofnaltrexone hydrochloride substituted for the naloxone hydrochloride ofExample 16.

EXAMPLE 20

The formulation of Example 16 was modified with 0.0067 mg/suppository ofnalmefene hydrochloride substituted for the naloxone hydrochloride ofExample 16.

EXAMPLE 21

The formulation of Example 16 was modified with 0.005 mg/suppository ofnalmefene hydrochloride substituted for the naloxone hydrochloride ofExample 16.

1. An analgesic composition in parenteral unit dosage form or in a unitdosage form suitable for delivery via the mucosa comprising an amount ofbuprenorphine which is less than the effective dose required to achievepain relief and an amount of naloxone such that the ratio by weight ofbuprenorphine to naloxone is in the range of from 12.5:1 to 27.5:1,whereby the analgesic action of the buprenorphine is potentiated by thelow dose of naloxone.
 2. A composition as claimed in claim 1 wherein theunit dosage form contains an amount of naloxone such that the ratio byweight of buprenorphine to naloxone is in the range of from 15:1 to20:1.
 3. An analgesic composition as claimed in claim 1 in whichbuprenorphine is present in an amount of from 15 μg to 200 μg per unitdose.
 4. A composition as claimed in claim 3 wherein the unit dosageform contains an amount of naloxone such that the ratio by weight ofbuprenorphine to naloxone is in the range of from 15:1 to 20:1.
 5. Ananalgesic composition according to claim 3 which is in sublingual unitdosage form.